Analysis of Enhancer Activity of a Dinucleotide Repeat Polymorphism in the Neurotrophin-3 Gene and Its Association with Bipolar Disorder

Abstract

Growing evidence has implicated the possible involvement of neurotrophins in the pathogenesis of functional psychoses such as schizophrenia and bipolar disorder. Previous studies reported a significant association of a dinucleotide repeat polymorphism of the neurotrophin-3 (NTF3) gene with schizophrenia. The aims of the present study were to examine whether this polymorphism is associated with bipolar disorder and whether the polymorphic region has an enhancer/silencer effect on transcriptional activity in an allele-dependent manner. In an association analysis between the polymorphism and bipolar disorder in a Japanese sample of 88 patients and 98 controls matched for age, sex, and ethnicity, the distribution of alleles did not differ significantly between the two groups. pGL3-promoter luciferase reporter vectors containing the polymorphic region increased luciferase activity relative to empty pGL3-promoter vector in HeLa, IMR-32 (neuroblastoma) and Hs683 (glioma) cell lines; however, no significant difference was detected between alleles for either cell line. Our results suggest that the examined polymorphism has no major role in giving susceptibility to bipolar disorder. Although the polymorphic region may have an enhancer-like effect on transcriptional activity, we obtained no evidence for allele-dependent differential effects.

Genetic Variations of Human Neuropsin Gene and Psychiatric Disorders: Polymorphism Screening and Possible Association with Bipolar Disorder and Cognitive Functions

“…As negative control, an empty pGL3-Basic vector was simultaneously transfected in all the experiments. At 24 h after transfection, luciferase activity was measured using a Dual-Luciferase Reporter Assay System (Promega) and a Lumat LB 9507 luminometer (Berthold, Bad Wildbad, Germany), as described previously (Tadokoro et al, 2004;Okada et al, 2006). Firefly and Renilla luciferase activities were quantified sequentially as relative light unit (RLU) by addition of their respective substrates according to the protocol of the supplier.…”

A complex polymorphic region in the brain-derived neurotrophic factor (BDNF) gene confers susceptibility to bipolar disorder and affects transcriptional activity

“…At 24 h after transfection, luciferase activity was measured by using Dual-Luciferase Reporter Assay System (Promega, Tokyo, Japan) and a Lumat LB9507 luminometer (Berthold Technologies, Bad Wildbad, Germany), as described previously. 24 Firefly and renilla luciferase activities were quantified sequentially as relative light units (RLU) by addition of their respective substrates. The ratio of firefly RLU to renilla RLU of each sample was automatically computed.…”

Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction

“…BDNF and NT-3 have been proposed as susceptibility genes for major depressive disorder and schizophrenia (Lin and Tsai, 2004;Tadokoro et al, 2004;Schumacher et al, 2005) and for other neuropsychiatric disorders (Ribases et al, 2005;Liu et al, 2005). Administration of brainderived neurotrophic factor (BDNF-Mouse Genome Informatics) or neurotrophin-3 (NT3; NTF3-Mouse Genome Informatics) into the dentate gyrus or CA3 region of hippocampus causes antidepressantlike effects in the forced swim and learned helplessness tests (Shirayama et al, 2002) and activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects (Saarelainen et al, 2003).…”